ABSTRACT Niemann-Pick type C1 (NPC1) disease is a rare, neurodegenerative cholesterol storage disorder. Affected individuals typically present in early childhood with ataxia and progressive impairment of motor and intellectual function, and usually die in adolescence, though increasingly NPC disease is being recognized among the adult population with cognitive defects. There are currently no FDA-approved therapies for this progressively fatal neurodegenerative disorder. In preclinical studies, treatment with 2-hydroxypropyl-?-cyclodextrin (HP-?- CD) has been shown to reduce both cholesterol and sphingolipid storage and prolong survival, and has been advanced to clinical trials. A Phase 1/2a trial of intrathecal (IT) HP-?-CD was initiated at the NIH Clinical Center in January 2013, and in collaboration with Vtesse, Inc., an international, multisite Phase 2b/3 trial of IT VTS-270 (a specific formulation of HP-?-CD) was launched in September 2015. While IT delivery of VTS-270 in the clinical trials directly addresses the neurodegenerative component of NPC disease, visceral manifestations of the disease are left untreated. In infantile and juvenile forms of NPC disease, patients typically present with neonatal cholestasis or hepatosplenomegaly, and in severe cases may progress to liver failure. In older NPC patients, 2-3-fold chronic elevation of serum transaminases (ALT/AST) and liver inflammation are common. We hypothesize that reduction of hepatic cholesterol storage through intravenous (IV) delivery of VTS-270 will be effective in reducing liver inflammation in NPC1 patients. We will test this hypothesis by (1) performing a Phase 1/2a, open-label, single-center, randomized study of IV VTS-270 in human NPC1 subjects (? 3 years old) at the NIH Clinical Center, and (2) conducting a Phase 1/2a, open-label, multi-center, dose escalation study of IV VTS-270 to establish safety and potential clinical efficacy in treating cholestatic liver disease in infants (< 3 years old) with NPC1 at Johns Hopkins and Washington University sites. Our primary objective is to determine the safety and tolerability of intravenous VTS-270 in NPC1 disease. Secondary objectives will be to evaluate the efficacy of VTS-270 to reduce plasma cholestane-3?,5?,6?-triol, an NPC1-specific pharmacodynamic biomarker, and to normalize liver function tests, as well as the examination of exploratory lipid and protein biomarkers. Clinical efficacy will be evaluated by assessment of liver function tests, determination of liver size, and changes in liver histopathology. Biochemical efficacy will be assessed by measurement of plasma cholestane-3?,5?,6?-triol and other biomarkers. We anticipate that treatment with IV VTS-270 monthly will reduce liver inflammation and restore normal hepatic function. In both NPC groups, long-term treatment with IV VTS-270 would be expected to prevent liver fibrosis and lower risk of hepatocellular carcinoma.